In the treatment of hypertension, it is more important to maintain the blood pressure within a normal range on a consistent basis than to simply lower the blood pressure level itself, for reducing the risks of complications such as coronary heart diseases and cardiovascular diseases, e.g., stroke, heart failure and myocardial infarction. Accordingly, antihypertensive agents should be effective for long-term treatment of hypertension. Further, advanced therapy using a combination of two or more drugs having different pharmacological actions makes it possible to improve preventive or therapeutic effects, while lowering side effects arising from the long term administration of a single drug.
Notable antihypertensive drugs include diuretics, sympatholytic agents and vasodilators. Vasodilators are most widely prescribed antihypertensive drugs, and they are divided into several groups according to their pharmacological action which include ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists and calcium channel blockers.
Amlodipine is the generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate. Amlodipine besylate is currently marketed as Novasc (trade mark). Amlodipine is a long-acting calcium channel blocker which is useful in treating cardiovascular disorders such as agina, hypertension and congestive heart failure.
Losartan is the generic name for 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol, which has been disclosed in U.S. Pat. Nos. 5,608,075; 5,138,069; and 5,153,197. Losartan potassium is commercially available as Cozaar (trade mark). Losartan blocks the interaction of angiotensin II and its receptor, and is mainly used for treating hypertension, heart failure, ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), diabetic neuropathy and glaucoma, and also for preventing the progression of post-myocardial infarction heart failure.
The present inventors have found that a combined formulation which comprises amlodipine and losartan having different pharmacological activities is useful for preventing or treating cardiovascular disorders, and have developed such an amlodipine-losartan combined composition having optimized physical and chemical properties.